Modified hollow-fiber membrane

ABSTRACT

A modified hollow-fiber membrane which has improved surface hydrophilicity without increasing the amount of components released therefrom, is less apt to interact with living-body components, does not adsorb proteins, and is less apt to deteriorate in performance. The hollow-fiber membrane has a copolymer of 2-methacryloyloxyethylphosphorylcholine and other polymerizable vinyl monomer held on a surface of the membrane, the copolymer being present on the surface in a higher concentration than in other parts of the membrane. The modified hollow-fiber membrane is useful in medical applications such as hemodialysis and blood filtration and in the medical industry, food industry etc.

TECHNICAL FIELD

The present invention relates to a hollow-fiber membrane with a modifiedmembrane surface. More particularly, the present invention relates to ahollow fiber membrane of which the surface has been modified to controladsorption of proteins onto the surface or to suppress interaction ofblood components on the surface, and to a method for preparing thehollow-fiber membrane. The hollow fiber membrane of the presentinvention can be used as a membrane for medical treatment suitable forpurification of blood such as hemodialysis and blood filtration or as apermselective membrane used in the pharmaceutical industry or the foodindustry.

BACKGROUND ART

Hollow fiber membranes made from various materials are widely used aspermselective membranes for medical applications such as hemodialysisand blood filtration, as well as for the pharmaceutical industry, foodindustry, and the like. The hollow fiber membranes used in suchapplications must have superior mechanical strength and chemicalstability, possess easily controllable permeability, release a minimalamount of materials, exhibit almost no interaction with biologicalcomponents, and be safe for living bodies. However, there have been nohollow fiber membranes completely satisfying all of these requirements.

When the material is a synthetic polymer, for example, the surface isgenerally hydrophobic. Unduly weak hydrophilic properties tend to causethe material to react with blood components, cause the blood to easilycoagulate, and impair the permeability performance of the hollow fibermembrane due to adsorption of protein components. A study for providingthe hollow fiber membrane made from such a synthetic polymer withcompatibility with blood by incorporating a polymer with hydrophilicproperties has been undertaken. For instance, a permselective membranemade from a polysulfone-based polymer with a hydrophilic polymerincorporated therein and a method of manufacturing such a membrane havebeen proposed. Such a membrane, however, exhibits only poor wettingproperties and tends to coagulate blood due to decreased compatibilitywith blood, if the content of the hydrophilic polymer is small. On theother hand, if the content of the hydrophilic polymer is large, theamount of the hydrophilic polymer dissolved from the membrane increases,although the blood coagulation can be suppressed.

Japanese Patent Applications Laid-open No. S61-238306 and No. S63-97666disclose a method for preparing a polysulfone-based separation membranein which a membrane-forming raw material solution contains apolysulfone-based polymer, a hydrophilic polymer, and an additive actingas a non-solvent or a swelling agent on the polysulfone-based polymer.These patents, however, do not describe a method for reducingdissolution of hydrophilic polymers. Japanese Patent ApplicationsLaid-open No. S63-97205, S63-97634, and H04-300636 disclose a method ofreducing dissolution of hydrophilic polymers from the polysulfone-basedseparation membrane prepared by the above method by insolubilizing thehydrophilic polymers by means of a radiation treatment and/or a heattreatment of the membrane. However, this method impair compatibility ofthe membrane with blood, possibly due to the insolubility of thehydrophilic polymer caused by cross-linking. The membrane obtained bythis method contains the hydrophilic polymer in thick membrane areas(inner parts of membrane) as well, precluding the thick membrane areasfrom exhibiting required hydrophobicity.

Japanese Patent Applications Laid-open No. S61-402 and S62-38205disclose membranes containing a hydrophilic polymer only in the denselayer side. Japanese Patent Application Laid-open No. H04-300636discloses a membrane containing polyvinyl pyrrolidone present in ahigher concentration in the inner surface side than in other parts ofthe hollow fiber membrane. There patents, however, only describe thatthe hydrophilic polymers are present near the surface of the membranecoming into contact with blood, but do not describe any specificproperties of the polymers. In addition, no sufficient hydrophobicitycan be obtained in the thick membrane areas of these hollow fibermembranes.

Several researches are being undertaken with an objective of providinghollow fiber membranes with superior biological compatibility bymodifying the polymers so that the surface has not only hydrophilicproperties but also a structure similar to a biomembrane. Specifically,one such research contemplates improvement of biocompatibility of hollowfiber membranes by incorporating a copolymer of 2-methacryloyloxyethylphosphorylcholine and other monomers having a structure similar tophospholipids, major components forming biomembranes, into syntheticpolymer hollow fiber membranes.

Japanese Patent Application Laid-open No. H10-296063 discloses apolysulfone-based porous membrane and a method of manufacturing thesame. The porous membrane is produced using a mixed solution of acopolymer of 2-methacryloyloxyethyl phosphorylcholine and other monomersand a polysulfone as a membrane-forming raw material solution. Themembrane obtained by this method, however, contains the copolymer of2-methacryloyloxyethyl phosphorylcholine and other monomers in thickmembrane areas (inner parts of membrane) as well, precluding the thickmembrane areas from exhibiting hydrophobicity. In addition, thecopolymer may be dissolved or desorbed from the membrane.Incompatibility of the copolymer and the polysulfone resin is anotherproblem which limits the composition of the solvent used for preparingthe mixed solution.

Japanese Patent Application Laid-open No. H05-177119 discloses amembrane produced by coating the surface of a porous membrane made frompolyolefin or polyolefin fluoride with a copolymer of2-methacryloyloxyethyl phosphorylcholine and methacrylate. However, alarge amount of the copolymer, for example, an amount equivalent to 30%or more, preferably 50% or more, of the pore surface of the porousmembrane possessing 20 vol % or more void ratio, must be covered toobtain a sufficient effect. This causes the copolymer of2-methacryloyloxyethyl phosphorylcholine and methacrylate to be alsocoated over the pore surface inside the hollow fiber membrane,precluding the thick membrane areas from exhibiting hydrophobicity. Inaddition, the copolymer may be dissolved or desorbed from the membrane.

More recently, diversified and sophisticated functions have beendemanded of membranes. In the field of artificial dialysis, for example,countercurrent invasion of endotoxin from the dialysis fluid side causedby high performance membranes has been pointed out. To overcome thisproblem, development of a high performance membrane capable ofeliminating endotoxin and exhibiting no interaction with bloodcomponents is desired.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a hollow fiber membranewith a surface structure similar to the structure of biomembranes, witha surface exhibiting only small interaction with biological components,not adsorbing proteins, being free from deterioration in performance,and excelling in biocompatibility.

Another object of the present invention is to provide a hollow fibermembrane which can adsorb and trap foreign matters such as endotoxincountercurrently flowing from outside the hollow fiber in the thickmembrane areas.

The inventors of the present invention have conducted extensive studiesto achieve the above objects. As a result, the inventors have found thatone of these objects can be achieved if a copolymer of2-methacryloyloxyethyl phosphorylcholine (hereinafter referred to as“MPC”) and other vinyl-polymerizable monomers (the copolymer ishereinafter referred to as “MPC copolymer”) is held on the surface ofthe hollow fiber membrane so that the MPC copolymer is present in alarger concentration than in the other parts of the membrane. Thisfinding has led to the completion of the present invention.

Specifically, the present invention provides a modified hollow fibermembrane made from a synthetic polymer selected from the groupconsisting of polysulfone-based polymers, polycarbonate-based polymers,polyamide-based polymers, polyvinyl chloride-based polymers, polyvinylalcohol-based polymers, polyallylate-based polymers,polyacrylonitrile-based polymers, polyether-based polymers,polyester-based polymers, polyurethane-based polymers,polyacrylate-based polymers, polyolefin-based polymers, and fluorinatedpolyolefin-based polymers, and mixtures of these polymers, the hollowfiber membrane being modified with a copolymer of MPC and othervinyl-polymerizable monomers which is present on inside and/or outsidesurface of the hollow fiber membrane in a larger concentration than inthe other parts of the membrane.

The inventors have further found that the above other object can beachieved by forming the thick membrane areas of the hollow fibermembrane from a synthetic polymer having a contact angle in the range of50° to 100°.

The present invention further provides a method of preparing a modifiedhollow fiber membrane comprising, in a dry and wet spinning methodcomprising simultaneously discharging a hollow space inner solution fromthe inner side of double spinning nozzles and a synthetic polymersolution from the outer side of the double spinning nozzles andimmersing the spun yarns in a coagulation bath located below thespinning nozzles, characterized by using a solution prepared bydissolving 0.001–10 wt % of an MPC copolymer as the hollow space innersolution and/or as a coagulation bath solution. The present inventionfurther provides a method of preparing a modified hollow fiber membranecomprising passing a solution of 0.001–10 wt % of MPC copolymer througha hollow space of hollow fiber membrane made from a synthetic polymerand/or the outer side of the hollow fiber membrane, thereby causing thecopolymer to be adsorbed onto the surface of the hollow fiber membrane.

The present invention will be explained in more detail in the followingdescription, which is not intended to be limiting of the presentinvention.

Synthetic polymers used as raw materials for the hollow fiber membraneof the present invention include polysulfone-based polymers,polycarbonate-based polymers, polyamide-based polymers, polyvinylchloride-based polymers, polyvinyl alcohol-based polymers,polyallylate-based polymers, polyacrylonitrile-based polymers,polyether-based polymers, polyester-based polymers, polyurethane-basedpolymers, polyacrylate-based polymers, polyolefin-based polymers, andfluorinated polyolefin-based polymers, and mixtures of these polymers.The term “-based polymers” used in the present invention indicates thatthe polymers include not only homopolymers but also copolymers. Anymonomers can be used as the components for the copolymers inasmuch asthe resulting copolymers retain the characteristics of their basepolymer.

Specific examples of the polymers include polysulfone, polyethersulfone, polyarylether sulfone, polyallylate-polyether sulfone-polymeralloy, polycarbonate, polyvinyl chloride, vinyl chloride-vinyl acetatecopolymer, ethylene-vinyl alcohol copolymer, polyethylene terephthalate,polybuthylene terephthalate, polyamide 6, polyamide 66,polyacrylonitrile, poly(methyl acrylate), poly(butyl acrylate),polyethylene, polypropylene, poly-4-methylpentene-1, polyvinylidenefluoride, and the like.

In addition, a synthetic polymer having a contact angle in the range of50° to 100° is used as a material for forming the thick membrane areasof the hollow fiber membrane to achieve the object of the presentinvention. The contact angle as used in the present invention is acontact angle with water and can be determined by forming a flat platefrom the synthetic polymer used for the thick membrane areas, placing awater drop on the surface, and measuring the angle made by the syntheticpolymer and the water surface. The lower the water contact angle, thehigher the hydrophilic properties; and the higher the water contactangle, the higher the hydrophobic properties. When the synthetic polymerforming the thick membrane areas is a polymer mixture, at least themajor polymer component forming the thick membrane areas must have acontact angle between 50° and 100°.

Endotoxin which is a pollutant in dialysis fluids has a lipid A site, astructure derived from a fatty acid, and tends to be adsorbed on thesurface of hydrophobic polymers due to the hydrophobic properties ofthis site. Since foreign matters such as endotoxin contained in thedialysis fluid on the outside surface side of hollow fiber membrane canbe efficiently adsorbed by forming the thick membrane areas from asynthetic polymer having a contact angle of 50° to 100°, pollution ofblood due to reverse permeation of endotoxin to the inside surface sidecan be prevented. If the contact angle is greater than 100°, theadsorptive activity of blood proteins tends to change. Therefore, themajor raw material for the membrane forming the thick membrane areaspreferably has a contact angle between 50° and 100°.

Any synthetic polymers having a contact angle of this range and capableof forming a hollow fiber membrane can be used as raw materials in thepresent invention. Examples include polysulfone-based polymers,polycarbonate-based polymers, polyvinyl chloride-based polymers,polyallylate-based polymers, polyether-based polymers, polyester-basedpolymers, polyurethane-based polymers, polyacrylate-based polymers,polyolefin-based polymers, and fluorinated polyolefin-based polymers,and mixtures of these polymers. The term “-basedpolymers” used hereindicates that the polymers include not only homopolymers but alsocopolymers. Any monomers can be used as the components for thecopolymers inasmuch as the resulting copolymers retain thecharacteristics of their base polymer.

Specific examples of the polymers include polysulfone, polyethersulfone, polyarylether sulfone, polyallylate-polyether sulfone-polymeralloy, polycarbonate, polyvinyl chloride, vinyl chloride-vinyl acetatecopolymer, polyethylene terephthalate, polybuthylene terephthalate,poly(methyl acrylate), poly(butyl acrylate), polyethylene,polypropylene, poly-4-methylpentene-1, polyvinylidene fluoride, and thelike.

As the other vinyl-polymerizable monomer for forming copolymers withMPC, one or more vinyl-polymerizable monomers selected from the groupconsisting of vinyl pyrrolidone, styrene, and (meth)acrylate derivativescan be used. The (meth)acrylate derivatives preferably used asvinyl-polymerizable monomers include the compounds of the followingformulas (1), (2), or (3),

wherein R¹ is a hydrogen atom or a methyl group and R² is a hydrogenatom or an aliphatic or aromatic hydrocarbon group having 1–20 carbonatoms.

wherein R³ is a hydrogen atom or a methyl group, R⁴ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and A indicates O or OR⁵O, wherein R⁵ is a substituted or unsubstitutedalkylene group having 1–10 carbon atoms,

wherein R⁶ is a hydrogen atom or a methyl group, R⁸ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and R⁷ is a substituted or unsubstituted alkylene group having 1–10carbon atoms.

Suitable monomers are selected according to the characteristics desiredfor the copolymer.

As specific compounds, butyl methacrylate, benzyl methacrylate,methacryloyloxyethyl phenylcarbamate, phenyl methacryloyloxyethylcarbamate, and the like can be given.

If the monomer unit content of MPC in the copolymer, which is the ratioof MPC (A mols) to the total of MPC (A mols) and othervinyl-polymerizable monomer components (B mols), A/(A+B), is small, thecopolymer tends to exhibit insufficient biocompatibility and hydrophilicproperties. If the MPC monomer unit content is large, on the other hand,the copolymer exhibits increased solubility in water and decreasedsolubility in organic solvents, resulting in an increase in the amountof membrane materials dissolved in water or other problems such aslimited application of the hollow fiber membrane. For this reason, themonomer unit content of MPC in the present invention is preferably from0.05 to 0.95, and more preferably from 0.1 to 0.5.

Although the biocompatibility on the surface of the hollow fibermembrane of the present invention is affected by the type ofvinyl-polymerizable monomers copolymerized with MPC and the MPC monomerunit content, the biocompatibility is basically determined by the amountof MPC present on the membrane surface. Such an amount of MPC monomerunits can be determined by analyzing the surface of hollow fibermembrane by X-ray photoelectron spectroscopy. Since the ratio ofelements present near the surface can be determined by the X-rayphotoelectron spectroscopy, the MPC monomer unit concentration (theweight of MPC monomer unit/the weight of membrane) near the surface canbe calculated from the chemical formula of the MPC copolymer and thechemical formula of polymer forming the membrane. Since this is theconcentration near the surface of the membrane, the value is employed asthe MPC monomer unit concentration on the membrane surface. The MPCmonomer unit concentration on the membrane surface determined in thismanner is preferably 5 wt % or more, and more preferably 8 wt % or morefor the hollow fiber membrane to exhibit biocompatibility. To increasethe MPC monomer unit concentration on the membrane surface, not only theconcentration of MPC monomer unit in the copolymer but also theconcentration of MPC copolymer per unit weight of membrane must beincreased. This leads to an increase in the amount of dissolvedmaterials. Therefore, the MPC monomer unit content is preferably 50 wt %or less, and more preferably 40 wt % or less.

The MPC copolymer may be present in a concentration higher than theother part of the membrane either on the inside surface or the outsidesurface, or on both surfaces of the hollow fiber membrane. The surfaceon which the MPC copolymer is present in a higher concentration than inother parts of the hollow fiber membrane is suitably selected accordingto the application or the manner of use of the hollow fiber membrane.

In the hollow fiber membrane described in Japanese Patent ApplicationLaid-open No. H05-177119, MPC copolymer not only covers porous surfaceof the porous hollow fiber membrane, but also is present on the poroussurface of inner parts of membrane (thick membrane areas). On the otherhand, in the present invention the amount of MPC copolymer present inpores in the inner parts of membrane (thick membrane areas) should be assmall as possible, but the MPC copolymer should be unevenly distributedonly on the surface of the hollow fiber membrane.

The MPC copolymer can be unevenly distributed on the surface of themembrane by adjusting the molecular weight of the MPC copolymer held onthe surface or by adjusting the membrane structure such as a void ratio,pore diameter, and the like of the hollow fiber membrane.

Because the MPC copolymer is unevenly distributed on the surface of themembrane in the present invention, the concentration of the MPC monomerunit on the surface of the hollow fiber membrane can be maintainedsufficiently high, notwithstanding a very small concentration of the MPCcopolymer per unit weight of the membrane (bulk concentration) The bulkconcentration may be in the range of 0.001–1.0 wt %, preferably 0.05–0.5wt %. The bulk concentration of MPC copolymer can be determined bypreparing a sufficiently washed and dried sample of hollow fibermembrane and analyzing fragments derived from MPC in this sample bypyrolysis gas chromatography.

The MPC copolymer is used as a solution in manufacturing the hollowfiber membrane of the present invention. The MPC copolymer may have ashigh molecular weight as possible as long as the polymer is dissolved inthe solvent without problem. If the molecular weight is too small, theMPC copolymer tends to liquate out or be released from the membrane. Inmanufacturing the hollow fiber membrane of the present invention, thesolution of MPC copolymer is caused to come into contact with thematerial of the membrane from the inside and/or outside surfaces of thehollow fiber membrane. If the molecular weight of the MPC copolymer istoo small, the MPC copolymer is diffused in the membrane so that the MPCcopolymer is incorporated all over the membrane. Thus, the MPC copolymerwith such a small molecular weight cannot achieve the feature of thepresent invention that the hydrophilic property polymer is unevenlydistributed over the inside and/or outside surfaces of the membrane. Forthese reasons, the MPC copolymer has a molecular weight preferably 5,000or more, and more preferably 10,000 or more.

In manufacturing the hollow fiber membrane of the present invention, thesolution of MPC copolymer may be caused to come into contact with thematerial of the membrane from the inside and/or outside surfaces of thehollow fiber membrane, thereby causing the MPC copolymer to be held onthe inside and/or outside surfaces. The resulting hollow fiber membranehas a structure with a dense layer on the membrane surface on which theMPC copolymer is held. If the MPC copolymer molecule is large enough topreclude dispersion of the copolymer into the pores in membrane, theamount of the MPC copolymer incorporated into the inner parts ofmembrane (thick membrane areas) can be minimized. Form this point ofview, it is preferable that the hollow fiber membrane of the presentinvention have a structure with a dense layer on the membrane surface onwhich the MPC copolymer is held.

The hollow fiber membrane of the present invention having thick membraneareas made from a synthetic polymer having a contact angle in the rangeof 50° to 100° can adsorb and trap foreign matters such as endotoxincountercurrently flowing from outside the hollow fiber. For this reason,the thick membrane areas preferably have a porous structure withdeveloped networks rather than a finger void structure havingindependent large voids. To obtain hollow fiber membrane with such astructure, additives such as tetraethylene glycol, polyvinylpyrrolidone, and the like can be added to the raw material solution forforming the membrane.

As described above, the hollow fiber membrane can be modified in thepresent invention by unevenly distributing the MPC copolymer on themembrane surface. Such a hollow fiber membrane can be obtained by amethod of causing the MPC copolymer adsorbed on the surface of apreviously manufactured hollow fiber membrane, as mentioned above, or bya method of unevenly distributing the MPC copolymer on the membranesurface when the membrane is manufactured.

A conventionally known dry and wet spinning method can be used forunevenly distributing the MPC copolymer on the membrane surface when themembrane is manufactured. Specifically, a raw material fluid for thepreparation of membrane and an hollow space inner fluid aresimultaneously discharged from tube-in-orifice type double spinningnozzles, spun yarns are caused to run in air, and immersed in acoagulation bath containing water as a major coagulation mediuminstalled under the spinning nozzles. The coagulated yarns are woundaround a reel. The wound hollow fiber membrane is washed to removeexcessive additives and solvents. Glycerin is added as required,followed by drying by dry heating and the like to obtain a hollow fibermembrane. To unevenly distribute the MPC copolymer on the inner surfaceduring the manufacture of membrane, an MPC copolymer solution is used asa hollow space inner solution. To unevenly distribute the MPC copolymeron the outer surface, on the other hand, the MPC copolymer solution isused as a coagulating solution.

The hollow fiber membrane obtained by these methods release only a verysmall amount of eluted materials. This is thought to be the result ofthe following mechanism of membrane structure formation. Specifically,the membrane-forming raw material solution and hollow space innersolution in which the MPC polymer is dissolved are brought to come intocontact at the moment when these solutions are discharged from spinningnozzles. This causes the membrane-forming raw material solution tocoagulate, while the MPC polymer is entangled with molecular chains ofthe synthetic polymer forming the hollow-fiber membrane or incorporatedinto dense structures near the inner surface, thereby firmlyimmobilizing the MPC polymer. Absence of extra MPC polymer inside themembrane is also thought to contribute to the very small amount ofeluted materials.

This method can be applied to any synthetic polymer which can beprepared into membranes by the dry wet spinning method. A polymersolution in which a synthetic polymer used as a membrane-formingmaterial and additives are uniformly dissolved in a solvent is used asthe membrane-forming raw material solution. A non-solvent for thesynthetic polymer or a mixture of such as a non-solvent and a solventcan be used as a hollow space inner solution which forms hollow areas.The performance of the obtained hollow-fiber membrane is generallycontrolled by the ratio of the non-solvent and the solvent in the hollowspace inner solution. Such a ratio is determined according to the objectof application.

As an MPC copolymer, a copolymer soluble in the hollow space innersolution and/or coagulating bath solution can be selected and used.

The concentration of the MPC copolymer in the hollow space innersolution and/or coagulating bath solution in the range of 0.001–10 wt %is sufficient for attaching the MPC copolymer to the membrane surfacenecessary for the hollow-fiber membrane to exhibit biocompatibility,with the range of 0.01–5 wt % being more preferable.

Various known methods of manufacturing hollow-fiber membranes can beused for previously preparing the hollow-fiber membrane to be modified.Any synthetic polymers to which these membrane-forming methods areapplicable can be used as the material for forming the hollow-fibermembrane. In this method, a solution for adsorption treatment preparedby dissolving the MPC copolymer in a suitable solvent is caused to comeinto contact with the membrane surface on which the MPC copolymer shouldbe unevenly distributed, thereby causing the MPC copolymer to beadsorbed. The MPC copolymer can be adsorbed using any appropriate methodsuch as a method of immersing the hollow fiber into the adsorbedsolution, a method of passing the adsorbed solution through the hollowspace or outside the hollow-fiber membrane, or a method of encapsulatingthe adsorbed solution into the hollow space or outside the hollow-fibermembrane. After that, excess copolymer and solvent are removed bywashing. Then, the product is dried, if necessary. These processing canbe carried out either in the module step when the hollow fiver has beenformed or in the step before formation of the hollow fiber. Theconcentration of the MPC copolymer in the adsorbed solution in the rangeof 0.001–10 wt % is sufficient for attaching the MPC copolymer to themembrane surface necessary for the hollow-fiber membrane to exhibitbiocompatibility, with the range of 0.01–5 wt % being more preferable.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in more detail by way ofworking examples and test examples, which should not be construed aslimiting the present invention.

(Measurement of Amount of Eluted Materials)

1.5 g of hollow fiber membrane was put into 150 ml of distilled waterand heated at 70° C. for one hour to obtain an extract. UV radiationabsorbance of the extract at a wavelength of 220–350 nm was measuredusing distilled water heated at 70° C. for one hour without adding thehollow fiber membrane as a control. The amount of eluted materials isindicated by the highest value of absorbance in the wavelength range of220–350 nm.

EXAMPLE 1

18 parts of polysulfone (“Ultrason S3010” manufactured by BASF) wasadded to a mixture of 57 parts of N,N-dimethylacetamide (DMAC) and 25parts of tetraethylene glycol (TEG). The mixture was stirred for 6 hoursat 60° C. and dissolved to obtain a membrane-forming raw materialsolution. The raw material solution maintained at a temperature of 45°C. was discharged from spinnerets with an annular orifice together witha 40% aqueous solution of DMAC, to which 1% of a copolymer of MPC andmethacryloyloxyethyl phenyl carbamate (MPC monomer unit content=0.31,molecular weight=109,000) was added as an internal coagulate solution.The spun raw material was passed through a water bath, placed 36 cmlower than the discharge nozzle, at 55° C. to be wound around a reel,and washed with hot water at 90° C. to remove any excess copolymer andthe solvent. The resulting hollow fiber membrane was confirmed to have awater permeability of 325 ml/m²·mmHg·hr, an MPC copolymer concentrationon the inner side surface of 13 wt %, and a bulk concentration of 0.25wt %. The absorbance of the extract obtained from the hollow fibermembrane determined by the elusion material measurement method was0.020.

EXAMPLE 2

A hollow fiber membrane was prepared in the same manner as in Example 1,except for using a 40% aqueous solution of DMAC, to which 1% of acopolymer of MPC and butyl methacryate (MPC monomer unit content=0.40,molecular weight=122,000) was added as an internal coagulate solution.The resulting hollow fiber membrane was confirmed to have a waterpermeability of 299 ml/m²·mmHg·hr, an MPC copolymer concentration on theinner side surface of 18 wt %, and a bulk concentration of 0.2 wt %. Theabsorbance of the extract obtained from the hollow fiber membranedetermined by the elusion material measurement method was 0.025.

EXAMPLE 3

A hollow fiber membrane was prepared in the same manner as in Example 1,except for using a 40% aqueous solution of DMAC, to which 1% of acopolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPC monomerunit content=0.28, molecular weight=160,000) was added as an internalcoagulate solution. The resulting hollow fiber membrane was confirmed tohave a water permeability of 280 ml/m²·mmHg·hr, an MPC copolymerconcentration on the inner side surface of 15 wt %, and a bulkconcentration of 0.3 wt %. The absorbance of the extract obtained fromthe hollow fiber membrane determined by the elusion material measurementmethod was 0.018.

EXAMPLE 4

A hollow fiber membrane was prepared in the same manner as in Example 1,except for using a 40% aqueous solution of DMAC, to which 1% of acopolymer of MPC and benzyl methacryate (MPC monomer unit content=0.29,molecular weight=132,000) was added as an internal coagulate solution.The resulting hollow fiber membrane was confirmed to have a waterpermeability of 310 ml/m²·mmHg·hr, an MPC copolymer concentration on theinner side surface of 14 wt %, and a bulk concentration of 0.25 wt %.The absorbance of the extract obtained from the hollow fiber membranedetermined by the elusion material measurement method was 0.019.

EXAMPLE 5

A hollow fiber membrane was prepared in the same manner as in Example 1,except for using a 40% aqueous solution of DMAC as an internal coagulatesolution. The resulting hollow fiber membrane was dipped into a 40%aqueous solution of ethanol, to which 1% of a copolymer of MPC andphenyl methacryloyloxyethyl carbamate (MPC monomer unit content=0.31,molecular weight=109,000) was added, to adsorb the MPC copolymer. Then,the hollow fiber membrane was washed with hot water at 90° C. to removeany excess copolymer and ethanol. The resulting hollow fiber membranewas confirmed to have a water permeability of 330 ml/m²·mmHg·hr, an MPCcopolymer concentration on the inner side surface of 12 wt %, and a bulkconcentration of 0.4 wt %. The absorbance of the extract obtained fromthe hollow fiber membrane determined by the elusion material measurementmethod was 0.015.

EXAMPLE 6

18 parts of polysulfone (“Ultrason S3010” manufactured by BASF) and 3parts of polyvinyl pyrrolidone (“Plasdone K90” manufactured by ISP) wereadded to 79 parts of DMAC. The mixture was stirred for 6 hours at 60° C.and dissolved to obtain a membrane-forming raw material solution. Theraw material solution maintained at a temperature of 45° C. wasdischarged from spinnerets with an annular orifice together with a 40%aqueous solution of DMAC, to which 1% of a copolymer of MPC andmethacryloyloxyethyl phenyl carbamate (MPC monomer unit content=0.31,molecular weight=109,000) was added as an internal coagulate solution.The spun raw material was passed through a water bath, placed 36 cmlower than the discharge nozzle, at 55° C. to be wound around a reel,and washed with hot water at 90° C. to remove any excess copolymer andthe solvent. The resulting hollow fiber membrane was confirmed to have awater permeability of 142 ml/m²·mmHg·hr, an MPC copolymer concentrationon the inner side surface of 17 wt %, and a bulk concentration of 0.1 wt%. The absorbance of the extract obtained from the hollow fiber membranewas 0.022.

EXAMPLE 7

A polyacrylonitrile-based synthetic polymer made from 92 parts ofpolyacrylonitrile, 6 parts of methyl acrylate, 1.5 parts of acrylicacid, and 0.5 part of methallylsulfonic acid was added to 79 parts ofDMAC. The mixture was stirred for 6 hours at 60° C. and dissolved toobtain a membrane-forming raw material solution. The raw materialsolution maintained at a temperature of 45° C. was discharged fromspinnerets with an annular orifice together with a 40% aqueous solutionof DMAC, to which 1% of a copolymer of MPC and methacryloyloxyethylphenyl carbamate (MPC monomer unit content=0.31, molecularweight=109,000) was added as an internal coagulate solution. The spunraw material was passed through a water bath, placed 36 cm lower thanthe discharge nozzle, at 55° C. to be wound around a reel, and washedwith hot water at 90° C. to remove any excess copolymer and the solvent.The resulting hollow fiber membrane was confirmed to have a waterpermeability of 162 ml/m²·mmHg·hr, an MPC copolymer concentration on theinner side surface of 20 wt %, and a bulk concentration of 0.2 wt %. Theabsorbance of the extract obtained from the hollow fiber membranedetermined by the elusion material measurement method, was 0.022.

EXAMPLE 8

High density polyethylene was melt-spun using spinnerets having anannular orifice at 165° C. The resulting non-drawn yarns were annealedon a roller heated at 115° C. and drawn at 25° C. (cold drawing) by 30%and at 80° C. (hot drawing) by 200%. The resulting hollow fiber membranehas a pore diameter of 0.01 μm. The resulting hollow fiber membrane wasdipped into a 40% aqueous solution of ethanol, to which 1% of acopolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPC monomerunit content=0.31, molecular weight=109,000) was added, to adsorb theMPC copolymer. Then, the hollow fiber membrane was washed with hot waterat 90° C. to remove an excess amount of the MPC copolymer and ethanol.The resulting hollow fiber membrane was confirmed to have a waterpermeability of 562 ml/m²·mmHg·hr, an MPC copolymer concentration on theinner side surface of 13 wt %, and a bulk concentration of 0.2 wt %. Theabsorbance of the extract obtained from the hollow fiber membrane was0.022.

COMPARATIVE EXAMPLE 1

A hollow fiber membrane was prepared in the same manner as in Example 1,except for using a 40% aqueous solution of DMAC as an internal coagulatesolution. The resulting hollow fiber membrane was confirmed to have awater permeability of 957 ml/m²·mmHg·hr, an MPC copolymer concentrationon the inner side surface of 0 wt %, and a bulk concentration of 0 wt %.

COMPARATIVE EXAMPLE 2

Next, as a Comparative Example a hollow fiber membrane was preparedaccording to the conventional method described in Japanese PatentApplication Laid-open No. H05-177119.

High density polyethylene was melt-spun using spinnerets having anannular orifice at 165° C. The resulting non-drawn yarns were annealedon a roller heated at 115° C. and drawn at 25° C. (cold drawing) by 50%and at 110° C. (hot drawing) by 300%. The resulting hollow fibermembrane has a pore diameter of 0.3 μm. The resulting hollow fibermembrane was dipped into a 40% aqueous solution of ethanol, to which 1%of a copolymer of MPC and phenyl methacryloyloxyethyl carbamate (MPCmonomer unit content=0.31, molecular weight=109,000) was added, toadsorb the MPC copolymer. Then, the hollow fiber membrane was washedwith hot water at 90° C. to remove an excess amount of the MPC copolymerand ethanol. The resulting hollow fiber membrane was confirmed to have awater permeability of 1,620 m/m²·mmHg·hr, an MPC copolymer concentrationon the inner side surface of 18 wt %, and a bulk concentration of 2.5 wt%. The extract obtained from the hollow fiber membrane exhibited a highabsorbance of 0.102.

TEST EXAMPLE 1

The ultra filtration rate (UFR) of bovine blood plasma was measuredusing the hollow fiber membrane obtained in Examples 1–8 and ComparativeExample 1. Specifically, a miniature module was prepared by bundling 140sheets of hollow fiber membrane with a length of 15 cm. Bovine bloodplasma to which heparin was added (heparin 5000 IU/l, proteinconcentration: 6.5 g/dl) was heated to 37° C. and passed through theminiature module at a linear velocity of 0.4 cm/sec at a membranepressure difference of 25 mmHg for 120 minutes to ultra filter the bloodplasma. The filtrate was sampled at 15, 30, 60, and 120 minutes. Theweight of the samples was measured to calculate the UFR. The results areshown in Table 1, which indicates that no performance deterioration ofUFR was seen in the hollow fiber membranes with MPC copolymer unevenlydistributed in the inner surface.

TABLE 1 Hollow fiber UFR (ml/m² · mmHg · hr) membrane 15 min 30 min 60min 120 min Example 1 41 42 41 42 Example 2 39 39 38 39 Example 3 37 3838 38 Example 4 42 42 41 42 Example 5 43 44 43 43 Example 6 36 35 37 35Example 7 28 29 28 29 Example 8 46 45 48 45 Comparative 30 28 23 18Example 1

TEST EXAMPLE 2

The permeability of endotoxin was measured using the hollow fibermembranes obtained in Examples 1–8 and Comparative Example 2.Specifically, a test solution with an endotoxin concentration of 100ng/ml was caused to permeate through a module with a membrane area of120 cm² from the dialysis fluid side to the blood side for 10 minutes ata rate of 5 ml/min. The filtrate was collected at the blood side outletto detect endotoxin using an endotoxin detecting LAL reagent (a helmetcrab corpuscle extract “HS-J” manufactured by Wako Pure ChemicalIndustries, Ltd.). As a result, no endotoxin was detected in thefiltrates of the hollow fiber membranes obtained in Examples 1–8,whereas 12 ng/ml of endotoxin was detected in the filtrate of the hollowfiber membrane obtained in Comparative Example 2.

TEST EXAMPLE 3

The thrombocytes adhesion to the hollow fiber membranes obtained inExamples 1–8 and Comparative Example 1 was evaluated. Specifically, aminiature module was prepared by bundling 28 sheets of hollow fibermembrane with a length of 14 cm. 7 cc of fresh human blood to whichheparin was added was passed through the module in 5 minutes, followingwhich 10 cc of a physiological saline solution was caused to flow toremove blood. Next, the hollow fiber membrane was cut into short piecesof 2 to 3 mm in length, which were put into a physiological salinesolution containing 0.5% Triton X-100 (polyoxyethylene (10) octylphenylether). The mixture was irradiated with supersonic waves. Isolatedlactic acid dehydrogenase (LDH) was quantitatively determined. Since theLDH is an enzyme present in cell membranes and almost all cells adheringto the membrane surface have been confirmed to be thrombocytes byelectron microscope observation, the determined LDH value was used forrelative evaluation of thrombocytes adhered to the membrane surface. Theresults are shown in Table 2, which indicates that only a small amountof thrombocytes have adhered to the surface of the hollow fibermembranes with MPC copolymer unevenly distributed in the inner surface.

TABLE 2 Hollow fiber LDH released from hollow fiber membrane membrane(unit/m²) Example 1 7.7 Example 2 8.2 Example 3 5.5 Example 4 7.0Example 5 8.0 Example 6 3.4 Example 7 2.4 Example 8 5.4 Comparative 34Example 1

INDUSTRIAL APPLICABILITY

Because the hollow fiber membrane of the present invention comprises acopolymer of 2-methacryloyloxyethyl phosphorylcholine and othervinyl-polymerizable monomers unevenly distributed inside and/or outsidethe surface of the membrane, the membrane surface can be modifiedwithout increasing materials dissolved out from the membrane.Specifically, the membrane releases or dissolves out the least amount ofmaterials, does not suffer from deterioration of its performance,activates thrombocytes very slightly, produces filtrate containing nodetected endotoxin, and is useful in medical application such ashemodialysis and blood filtration or as a permselective membrane used inthe pharmaceutical industry and the food industry.

1. A method of preparing a hollow fiber membrane made from a synthetichydrophobic polymer which holds a copolymer of 2-methacryloyloxyethylphosphorylcholine and other vinyl-polymerizable monomers on the surfacethereof, wherein said copolymer is present in the pores in the innerparts of the membrane only in a low amount and wherein the copolymer isunevenly distributed on the surface of the hollow fiber membranecomprising simultaneously discharging a hollow space inner solution fromthe inner side of double spinning nozzles and a synthetic polymersolution from the outer side of the double spinning nozzles andimmersing the spun yarns into a coagulation bath located below thespinning nozzles, wherein a solution prepared by dissolving 0.001–10 wt% of a copolymer of 2 -methacryloyloxyethyl phosphorylcholine and othervinyl-polymerizable monomers is used as the hollow space inner solution.2. The process according to claim 1, wherein the synthetic polymer ofsaid hollow fiber membrane is selected from the group consisting ofpolysulfone-based, polycarbonate-based, polyamide-based, polyvinylchloride-based, polyvinyl alcohol-based, polyallylate-based,polyacrylonitrile-based, polyether-based, polyester-based,polyurethane-based, and polyacrylate-based polymers and mixtures ofthese polymers.
 3. The process according to claim 1, wherein thesynthetic polymer of said hollow fiber membrane is a mixture ofpolysulfone and/or polyether sulfone and polyvinyl pyrrolidone.
 4. Theprocess according to claim 1, wherein the synthetic polymer formingthick membrane parts in the hollow fiber membrane is a synthetic polymerhaving a contact angle in the range of 50° to 100°.
 5. The processaccording to claim 1, wherein the copolymer held on the surface of themembrane has a monomer unit content of 2-methacryloyloxyethylphosphoryicholine in the range of 0.05 to 0.95.
 6. The process accordingto claim 1, wherein the monomer unit concentration of2-methacryloyloxyethyl phosphorylcholine on the surface of the membraneis 5 wt % or more.
 7. The process according to claim 1, wherein theother vinyl-polymerizable monomer in the copolymer held on the surfaceof the membrane is at least one compound selected from the groupconsisting of vinyl pyrrolidone, styrene, and (meth)acrylatederivatives.
 8. The process according to claim 7, wherein the(meth)acrylate derivative is a compound selected from the components ofthe following formulas (1), (2), and (3),

wherein R¹ is a hydrogen atom or a methyl group and R² is a hydrogenatom or an aliphatic or aromatic hydrocarbon group having 1–20 carbonatoms,

wherein R³ is a hydrogen atom or a methyl group, R⁴ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and A indicates O or OR⁵O, wherein R⁵ is a substituted or unsubstitutedalkylene group having 1–10 carbon atoms,

wherein R⁶ is a hydrogen atom or a methyl group, R⁸ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and R⁷ is a substituted or unsubstituted alkylene group having 1–10carbon atoms.
 9. A method of preparing a hollow fiber membranecomprising a synthetic hydrophobic polymer which holds a copolymer of2-methacryloyloxyethyl phosphorylcholine and other vinyl-polymerizablemonomers on the surface thereof, wherein said copolymer is unevenlydistributed on the surface of the membrane, and wherein theconcentration of the copolymer per unit weight of the membrane (bulkconcentration) is 0.001–1.0 wt %, said method comprising simultaneouslydischarging a hollow space inner solution from the inner side of doublespinning nozzles and a synthetic polymer solution from the outer side ofthe double spinning nozzles and immersing the spun yarns into acoagulation bath located below the spinning nozzles, wherein a solutionprepared by dissolving 0.001–10 wt % of a copolymer of2-methacryloyloxyethyl phosphorylcholine and other vinyl-polymerizablemonomers is used as the hollow space inner solution.
 10. The processaccording to claim 9, wherein the synthetic polymer is selected from thegroup consisting of polysulfone-based, polycarbonate-based,polyamide-based, polyvinyl chloride-based, polyvinyl alcohol-based,polyallylate-based, polyacrylonitrile-based, polyether-based,polyester-based, polyurethane-based, and polyacrylate-based polymers andmixtures of these polymers.
 11. The process according to claim 9,wherein the synthetic polymer is a mixture of polysulfone and/orpolyether sulfone and polyvinyl pyrrolidone.
 12. The process accordingto claim 9, wherein the synthetic polymer forming thick membrane partsin the hollow fiber membrane is a synthetic polymer having a contactangle in the range of 50° to 10°.
 13. The process according to claim 9,wherein the copolymer held on the surface of the membrane has a monomerunit content of 2-methacryloyloxyethyl phosphorylcholine in the range of0.05 to 0.95 and said bulk concentration of said copolymer is 0.05–0.5wt %.
 14. The process according to claim 9, wherein the othervinyl-polymerizable monomer in the copolymer held on the surface of themembrane is at least one compound selected from the group consisting ofvinyl pyrrolidone, styrene, and (meth)acrylate derivatives.
 15. Theprocess according to claim 14, wherein the (meth)acrylate derivative isa compound selected from the components of the following formulas (1),(2), and (3),

wherein R¹ is a hydrogen atom or a methyl group and R² is a hydrogenatom or an aliphatic or aromatic hydrocarbon group having 1–20 carbonatoms,

wherein R³ is a hydrogen atom or a methyl group, R⁴ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and A indicates O or OR⁵O, wherein R⁵ is a substituted or unsubstitutedalkylene group having 1–10 carbon atoms,

wherein R⁶ is a hydrogen atom or a methyl group, R⁸ is a hydrogen atomor an aliphatic or aromatic hydrocarbon group having 1–20 carbon atoms,and R⁷ is a substituted or unsubstituted alkylene group having 1–10carbon atoms.